Unraveling the role of flotillin-1 in driving hepatocellular carcinoma progression through transcription factor E3-mediated Golgi stress response.

In this editorial, we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology. The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma (HCC) progression. HCC is currently considered one of the major causes of global cancer-associated deaths, underscoring the critical need for novel therapeutic targets. Growing evidence underlines the role of the lipid raft protein flotillin-1 (FLOT1) in cancer, whose dysregulation drives tumor cell growth and survival. However, the regulatory role of FLOT1 on Golgi apparatus function in HCC is unknown. In this study, Zhang et al elucidated a pivotal mechanism by which FLOT1 promotes HCC progression through activation of transcription factor E3-mediated Golgi stress response. The study reveals that FLOT1 inhibits the mechanistic target of rapamycin complexes 1 and 2 by ubiquitination, facilitating transcription factor E3 dephosphorylation, nuclear translocation, and subsequent upregulation of Golgi stress-associated genes, thereby leading to enhanced HCC cell growth and invasive capacity. These findings obtained in vitro/in vivo highlight the interplay between FLOT1 and Golgi homeostasis in HCC. Targeting FLOT1 may offer a new strategy for the treatment of HCC.